Cenobamate (Xcopri)
cenobamate — tetrazole-derived carbamate antiseizure medication
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Focal-onset (partial-onset) seizures | Adults (≥18 years) | Monotherapy or adjunctive | FDA Approved |
| Focal-onset seizures with or without secondary generalization | Adults with history of failure of ≥2 ASMs | Adjunctive only | EMA Approved |
Cenobamate was approved by the FDA in November 2019 for focal-onset seizures in adults, initially as adjunctive therapy. Based on population pharmacokinetic analyses demonstrating similar exposure in monotherapy and adjunctive settings, the labeling does not restrict use to adjunctive therapy, effectively permitting monotherapy. The EMA approved cenobamate (marketed as Ontozry) in March 2021 with a narrower adjunctive-only indication in patients who have failed at least two prior antiseizure medications. Pediatric efficacy and safety have not been established; post-marketing studies in children aged 2–17 years are required by the FDA.
Primary generalized tonic-clonic seizures: Limited case series and retrospective data suggest potential benefit, but no controlled trial evidence exists. Evidence quality: Very low.
Neuropathic pain: Preclinical data show analgesic activity in animal models; no published human clinical trials for this indication. Evidence quality: Very low.
Dosing
Adult Dosing — By Clinical Scenario
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Focal epilepsy — new adjunctive therapy | 12.5 mg once daily | 200 mg once daily | 400 mg once daily | Titrate q2 weeks: 12.5 → 25 → 50 → 100 → 150 → 200 mg/day over 10 weeks Do not exceed titration schedule due to DRESS risk |
| Focal epilepsy — monotherapy initiation | 12.5 mg once daily | 200 mg once daily | 400 mg once daily | Same titration as adjunctive; withdraw prior ASMs gradually after target dose reached Monotherapy PK exposure equivalent to adjunctive (FDA PI) |
| Drug-resistant focal epilepsy — higher-dose optimization | 12.5 mg once daily | 200–400 mg once daily | 400 mg once daily | After reaching 200 mg, increase by 50 mg q2 weeks if needed; higher seizure freedom rates observed at 400 mg Reduce concomitant sodium channel blockers to improve tolerability |
| Hepatic impairment (Child-Pugh A or B) | 12.5 mg once daily | Per clinical response | 200 mg once daily | AUC increased 1.9-fold (mild) and 2.3-fold (moderate) vs healthy controls Avoid in severe hepatic impairment (Child-Pugh C); AUC 4.2-fold higher |
| Renal impairment (CrCl 15–89 mL/min) | 12.5 mg once daily | Per clinical response | 400 mg once daily | AUC increased 1.4–1.5-fold in mild–moderate impairment; dose reduction may be considered Not recommended in ESRD (CrCl <15 mL/min) on dialysis; dialysis clearance unknown |
The slow biweekly titration schedule starting at 12.5 mg is mandatory, not merely recommended. In early-phase studies with rapid weekly titration, three cases of DRESS occurred including one fatality. The open-label C021 safety study (n = 1,339) using the recommended slow titration reported zero DRESS cases, validating this approach. Never exceed the titration schedule, even in treatment-urgent scenarios.
Cenobamate tablets may be taken whole, crushed and mixed with 25 mL water for oral suspension, or crushed and administered via nasogastric tube. Bioequivalence has been confirmed across all three routes. The crushed-tablet suspension should be consumed immediately and not stored.
Pharmacology
Mechanism of Action
Cenobamate is a tetrazole-derived carbamate with a dual mechanism of antiseizure activity. It preferentially inhibits the persistent component of voltage-gated sodium currents, which is the fraction responsible for sustained repetitive neuronal firing during seizures. Unlike many traditional sodium channel blockers that primarily target transient sodium currents, cenobamate’s selectivity for persistent currents may account for its differentiated efficacy profile. Additionally, cenobamate acts as a positive allosteric modulator of GABAA receptors at a binding site distinct from the benzodiazepine site. This dual action on both excitatory sodium channels and inhibitory GABAergic transmission may contribute to the unusually high seizure freedom rates observed in clinical trials compared with other third-generation antiseizure medications.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | ≥88% oral bioavailability; Tmax 1–4 h (intact tablet), 0.5 h (crushed) | High and reliable absorption; food has no clinically significant effect; take with or without food at any time of day |
| Distribution | Vd/F ≈ 40–50 L; 60% protein-bound (albumin); concentration-independent | Moderate distribution volume; displacement interactions unlikely given concentration-independent binding |
| Metabolism | Extensive; glucuronidation (UGT2B7, UGT2B4) + oxidation (CYP2E1, CYP2A6, CYP2B6, minor CYP2C19, CYP3A4/5); parent drug >98% of plasma radioactivity | Inhibits CYP2C19, induces CYP3A4 and CYP2B6; important for drug interactions with phenytoin, oral contraceptives, and CYP3A substrates |
| Elimination | t½ 50–60 h; CL/F 0.45–0.63 L/h; 87.8% urine, 5.2% feces; only 6.8% excreted as unchanged drug | Long half-life supports once-daily dosing; steady-state reached in ~2 weeks; dose-dependent clearance (non-linear pharmacokinetics) |
Side Effects
Adverse reaction data are from pooled analysis of two pivotal placebo-controlled trials (Study C013 and Study C017; n = 442 cenobamate, n = 216 placebo). Most adverse effects are dose-dependent and CNS-related. Incidence figures represent the pooled rate across the 200 mg dose group unless specified; dose-stratified data (100 mg/200 mg/400 mg vs placebo) are shown where clinically relevant.
| Adverse Effect | Incidence (100 / 200 / 400 mg) | Clinical Note |
|---|---|---|
| Somnolence | 19% / 22% / 37% vs 11% placebo | Dose-dependent; typically improves over 2–4 weeks; additive with CNS depressants and alcohol |
| Dizziness | 18% / 22% / 33% vs 15% placebo | Dose-dependent; advise patients to avoid driving until effect is known |
| Fatigue | 12% / 14% / 24% vs 7% placebo | Part of a broader fatigue-related cluster including asthenia, malaise, hypersomnia, and lethargy |
| Diplopia | 6% / 7% / 15% vs 2% placebo | May indicate excessive sodium channel blockade when co-prescribed with carbamazepine or lacosamide |
| Headache | 10% / 12% / 10% vs 9% placebo | Not clearly dose-dependent; generally mild and self-limiting |
| Adverse Effect | Incidence (200 mg group) | Clinical Note |
|---|---|---|
| Nausea | 6% vs 3% placebo | Usually transient; not dose-limiting in most patients |
| Balance disorder | 5% vs 1% placebo | Part of the gait/coordination disturbance cluster; dose-dependent (9% at 400 mg) |
| Nystagmus | 7% vs 0% placebo | Clinical sign of CNS toxicity; consider dose reduction or concomitant ASM adjustment |
| Constipation | 4% vs 0% placebo | More common at higher doses (8% at 400 mg) |
| Vomiting | 4% vs 0% placebo | Dose-dependent; 5% at 400 mg |
| Gait disturbance | 3% vs 1% placebo | Strongly dose-dependent (8% at 400 mg); may improve with concomitant ASM dose reduction |
| Ataxia | 3% vs 2% placebo | Rises to 6% at 400 mg; one of the most common reasons for discontinuation |
| Dysarthria | 1% vs 0% placebo | Reaches 7% at 400 mg; reversible with dose adjustment |
| Confusional state | 2% vs 0% placebo | Part of cognitive dysfunction cluster; 3% at 400 mg |
| Decreased appetite | 1% vs 1% placebo | 5% at 400 mg; may contribute to weight loss |
| Tremor | 3% vs 1% placebo | Predominantly at 200 mg dose |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| DRESS / Multiorgan Hypersensitivity | Rare (0 cases with slow titration in C021; 3 cases with rapid titration in early studies) | Typically within first 1–8 weeks (during titration) | Immediate discontinuation; do not rechallenge; one fatal case reported with rapid titration. Monitor for fever, rash, lymphadenopathy, organ involvement |
| QT Shortening | Dose-dependent: 31% had >20 ms shortening at 200 mg, 66% at 500 mg | Dose-dependent; present at steady state | Contraindicated in familial short QT syndrome; use caution with other QT-shortening drugs; QTc <300 ms not observed in studies |
| Suicidal Behavior and Ideation | AED class effect (~0.43% vs 0.24% placebo) | As early as 1 week after initiation | Monitor for depression, suicidal ideation, mood changes; counsel patients and caregivers; suicidal ideation reported in 2% (100 mg) and 1% (200 mg) vs 0% placebo |
| Hepatic Failure | Very rare (postmarketing reports) | Variable | Monitor hepatic function; ALT >3x ULN observed in up to 2.7% at 400 mg in Study C017; discontinue if hepatic failure suspected |
| Psychosis (Hallucinations, Delusions) | Very rare (postmarketing reports) | Variable | Evaluate for organic and drug-related causes; dose reduction or discontinuation; psychiatric consultation as needed |
| Severe Neurological Impairment (ataxia, gait disturbance) | Serious in ~2% of treated patients vs 0% placebo | Dose-dependent; typically during titration or at higher doses | Dose reduction; consider reducing concomitant sodium channel blockers; advise against driving and hazardous activities |
| Reason for Discontinuation | Incidence (≥1% in any group, > placebo) | Context |
|---|---|---|
| Ataxia | Most common reason at 400 mg | Strongly dose-dependent; often reduces with concomitant ASM adjustment |
| Dizziness | ≥1% across dose groups | Common early in treatment; usually attenuates |
| Somnolence | ≥1% across dose groups | CNS class effect; additive with benzodiazepines and other sedatives |
| Diplopia | ≥1% (predominantly at 400 mg) | May indicate pharmacodynamic interaction with sodium channel blockers |
| Nystagmus | ≥1% (predominantly at 400 mg) | Clinical marker of CNS saturation; warrants dose adjustment |
The most impactful strategy for improving tolerability at higher cenobamate doses is to reduce concomitant antiseizure medication doses, particularly other sodium channel blockers (carbamazepine, lacosamide, oxcarbazepine). In the C021 open-label safety study, 50% of patients remaining on cenobamate for more than one year were able to reduce their concomitant ASM burden. A proactive approach to dose adjustments of background therapy can significantly improve the therapeutic index of cenobamate.
Drug Interactions
Cenobamate has a complex interaction profile: it inhibits CYP2C19, induces CYP3A4 and CYP2B6, and has bidirectional interactions with several antiseizure medications. Cenobamate itself is metabolized primarily via UGT2B7 and multiple CYP isoenzymes; its own plasma levels are reduced by approximately 27–28% when co-administered with phenytoin but are not significantly affected by valproate, phenobarbital, or carbamazepine.
Several important co-prescribed drugs are not significantly affected by cenobamate. Population pharmacokinetic analyses confirmed no clinically meaningful interaction with valproic acid, levetiracetam (only 4–13% decrease), lacosamide, or warfarin (CYP2C9 substrate). This simplifies polytherapy decisions for patients already stabilized on these agents.
Monitoring
-
DRESS Surveillance
Every visit during first 8 weeks of titration
Routine Monitor for fever, rash, lymphadenopathy, facial swelling, or laboratory signs of organ involvement (eosinophilia, elevated transaminases). Early manifestations may present without rash. Highest risk during titration. -
Hepatic Function
Baseline, then periodically
Routine Check ALT, AST at baseline. ALT >3x ULN occurred in up to 2.7% of patients at 400 mg. Repeat if symptoms suggest hepatotoxicity (jaundice, fatigue, nausea). Postmarketing hepatic failure cases reported. -
Serum Potassium
Baseline, then periodically during titration
Routine Dose-related elevations >5 mEq/L observed in 8–17% of cenobamate-treated patients in trials (vs 5.6–7% placebo). Maximum values of 5.9 mEq/L reported. Check in patients on ACE inhibitors, potassium-sparing diuretics, or with renal impairment. -
Concomitant ASM Levels
Before and during cenobamate titration
Routine Phenytoin levels (up to 84% increase), phenobarbital levels (up to 37% increase), and lamotrigine levels (21–52% decrease) should be checked. Adjust concomitant doses proactively to prevent toxicity or breakthrough seizures. -
Mood and Suicidality
Every visit, ongoing
Routine AED class warning: screen for depression, anxiety, irritability, suicidal ideation, and behavioral changes. Risk observed as early as one week after initiation and persists throughout treatment. -
ECG (QT Interval)
Baseline if cardiac risk factors present
Trigger-based Dose-dependent QT shortening (mean –11 ms at 200 mg, –18 ms at 500 mg). Consider baseline ECG in patients with cardiac disease, family history of sudden death, or co-prescribed QT-shortening drugs. QTc below 300 ms has not been observed. -
Neurological Assessment
Each dose escalation and as needed
Trigger-based Assess for ataxia, gait disturbance, nystagmus, dysarthria, and cognitive changes. Dose-dependent neurological adverse reactions were the most common reason for discontinuation. May necessitate reducing concomitant ASMs.
Contraindications & Cautions
Absolute Contraindications
- Hypersensitivity to cenobamate or any inactive ingredient in the formulation (contains lactose monohydrate)
- Familial Short QT Syndrome — cenobamate causes dose-dependent QT shortening; this condition carries a baseline risk of sudden death and ventricular fibrillation, particularly when QTc falls below 300 ms
Relative Contraindications (Specialist Input Recommended)
- History of DRESS or severe cutaneous hypersensitivity to other ASMs — cross-reactivity is not established, but heightened vigilance during titration is warranted. Document risk-benefit discussion.
- Severe hepatic impairment (Child-Pugh C) — cenobamate AUC is 4.2-fold higher; use is not recommended by the manufacturer but may be considered in exceptional circumstances with specialist oversight and dose modification.
- End-stage renal disease on dialysis (CrCl <15 mL/min) — no data on dialysis clearance; use not recommended.
- Pregnancy — animal studies demonstrate embryofetal toxicity and neurobehavioral impairment in offspring at clinically relevant exposures. Weigh seizure control benefits against potential fetal risk. Encourage enrollment in NAAED Pregnancy Registry (1-888-233-2334).
Use with Caution
- Mild to moderate hepatic impairment — reduce maximum dose to 200 mg/day; AUC elevated 1.9–2.3-fold
- Mild to severe renal impairment (CrCl 15–89 mL/min) — AUC elevated 1.4–1.5-fold in mild-moderate impairment; severe RI (CrCl <30) did not show significant AUC change, but caution and dose reduction may still be considered per PI
- Elderly patients — start at low end of dosing range due to higher likelihood of decreased hepatic, renal, or cardiac function
- Concomitant QT-shortening drugs — potential synergistic QT shortening effect
- Patients with depression or history of suicidal behavior — AED class warning applies; monitor closely
- Concomitant phenytoin therapy — near-doubling of phenytoin levels mandates proactive dose reduction to avoid toxicity
- Substance use history — cenobamate is a Schedule V controlled substance with demonstrated abuse potential at supratherapeutic doses (400 mg); may cause physical dependence and withdrawal syndrome upon abrupt discontinuation
Antiepileptic drugs, including cenobamate, increase the risk of suicidal thoughts or behavior. Pooled analysis of 199 placebo-controlled trials of 11 AEDs showed approximately twice the risk of suicidal thinking or behavior (adjusted relative risk 1.8; 95% CI: 1.2–2.7) in AED-treated patients compared to placebo. The increased risk was observed as early as one week after starting treatment and persisted throughout the assessed treatment duration. Monitor all patients for emergence or worsening of depression, suicidal thoughts, or unusual changes in behavior.
Patient Counselling
Purpose of Therapy
Cenobamate is a once-daily antiseizure medication prescribed to reduce the frequency of focal (partial-onset) seizures. It works through two complementary pathways: stabilizing overactive electrical signals in the brain and enhancing the brain’s natural inhibitory system. It may be used alone or alongside other seizure medications. Clinical studies have shown that cenobamate can achieve meaningful seizure reduction in patients who have not responded adequately to other treatments, with some patients achieving complete seizure freedom.
How to Take
Take cenobamate once daily, with or without food, at approximately the same time each day. The dose will be started very low (12.5 mg) and increased gradually every two weeks over approximately 10 weeks. This slow increase is essential for safety and should not be rushed. Tablets may be swallowed whole or crushed and mixed with water if swallowing is difficult. If a dose is missed, take it as soon as remembered unless it is close to the next scheduled dose. Never stop cenobamate abruptly without medical guidance, as sudden withdrawal can trigger seizures.
Sources
- XCOPRI (cenobamate) tablets, for oral use, CV. Full Prescribing Information. SK Life Science, Inc. Revised 04/2024. FDA Label Primary regulatory source for all dosing, pharmacokinetic, safety, and interaction data in this monograph.
- Ontozry (cenobamate) Summary of Product Characteristics. Angelini Pharma S.p.A. EMA Approved March 2021. EMA EPAR European regulatory source; provides the narrower adjunctive-only indication for drug-resistant focal epilepsy.
- Chung SS, French JA, Kowalski J, et al. Randomized phase 2 study of adjunctive cenobamate in patients with uncontrolled focal seizures. Neurology. 2020;94(22):e2311–e2322. doi:10.1212/WNL.0000000000009530 Study C013: pivotal phase 2 RCT demonstrating 55.6% median seizure reduction and 28.3% seizure freedom rate at 200 mg/day.
- Krauss GL, Klein P, Brandt C, et al. Safety and efficacy of adjunctive cenobamate (YKP3089) in patients with uncontrolled focal seizures: a multicentre, double-blind, randomised, placebo-controlled, dose-response trial. Lancet Neurol. 2020;19(1):38–48. doi:10.1016/S1474-4422(19)30399-0 Study C017: pivotal phase 3 dose-response RCT across 100, 200, and 400 mg/day demonstrating 21% seizure freedom at 400 mg.
- Sperling MR, Klein P, Aboumatar S, et al. Cenobamate (YKP3089) as adjunctive treatment for uncontrolled focal seizures in a large, multicenter, open-label safety study. Epilepsia. 2020;61(6):1099–1108. doi:10.1111/epi.16529 Study C021: open-label safety study (n=1,339) validating the slow titration schedule; zero DRESS cases with recommended protocol.
- Klein P, Aboumatar S, Bhatt A, et al. Long-term efficacy and safety of adjunctive cenobamate in patients with uncontrolled focal seizures: open-label extension of a randomized clinical study. Epilepsia. 2022;63(9):2262–2275. doi:10.1111/epi.17338 C017 OLE: sustained efficacy over 48 months with 76.4% showing ≥50% seizure reduction and >15% achieving seizure freedom.
- Lattanzi S, Trinka E, Zaccara G, et al. Third-generation antiseizure medications for adjunctive treatment of focal-onset seizures in adults: a systematic review and network meta-analysis. Drugs. 2022;82(2):199–218. doi:10.1007/s40265-021-01661-4 Network meta-analysis showing cenobamate with statistically superior 50% responder rate compared to brivaracetam, lacosamide, perampanel, and eslicarbazepine.
- Steinhoff BJ, Sanchez-Alvarez JC, Grunig K, et al. Practical guidance for the management of adults receiving adjunctive cenobamate for the treatment of focal epilepsy—expert opinion. Epilepsy Behav. 2021;124:108318. doi:10.1016/j.yebeh.2021.108318 Expert consensus on practical cenobamate management including ASM co-medication adjustments and titration strategies.
- Roberti R, De Caro C, Iannone LF, et al. Pharmacology of cenobamate: mechanism of action, pharmacokinetics, drug–drug interactions, and tolerability. CNS Drugs. 2021;35(6):609–618. doi:10.1007/s40263-021-00819-8 Comprehensive pharmacology review detailing the dual sodium channel and GABAA receptor mechanism of action.
- Zaccara G, Lattanzi S, Leo A, Russo E. Critical appraisal of cenobamate as adjunctive treatment of focal seizures in adults. Neuropsychiatr Dis Treat. 2021;17:3567–3578. doi:10.2147/NDT.S299288 Review addressing pharmacodynamic selectivity for persistent sodium currents and clinical implications of the non-benzodiazepine GABAA site.
- Buckley CT, Bhatt A, Engasser JK, et al. Pharmacokinetics of cenobamate: results from single and multiple oral ascending-dose studies in healthy subjects. Clin Pharmacol Drug Dev. 2020;9(7):849–857. doi:10.1002/cpdd.801 Characterizes single- and multiple-dose PK including dose-proportional Cmax, non-linear AUC, and long terminal half-life across doses.
- Vashi M, Engasser JK, Gidal B. Pharmacokinetics of cenobamate as monotherapy compared with adjunctive therapy. Epilepsy Res. 2023;196:107208. doi:10.1016/j.eplepsyres.2023.107208 Population PK analysis confirming equivalent cenobamate exposure in monotherapy versus adjunctive therapy, supporting monotherapy labeling.
- Vashi M, Engasser JK, Ren Y, et al. Relative bioavailability of cenobamate administered as a crushed tablet, either orally or via nasogastric tube, versus an intact whole tablet. J Clin Pharmacol. 2024;64(10):1262–1270. doi:10.1002/jcph.2439 Bioequivalence study supporting the 2024 label update for crushed tablet and nasogastric tube administration.
- Beltrán-Corbellini Á, Toledano R, Gil-Nagel A, et al. Real-world safety and effectiveness of cenobamate in patients with focal onset seizures: outcomes from an Expanded Access Program. Epilepsia. 2023;64(9):2460–2472. doi:10.1111/epi.17701 Largest real-world cohort (n=170) confirming 63% responder rate and 13.3% seizure freedom in highly refractory epilepsy patients.